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Cited by 536Epigenetics and DNA MethylationGenomics and Chromatin DynamicsGenetic Syndromes and Imprinting

The DOI matches its Crossref record; 45 of the 47 references it cites were found in a registry or an index.

The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape

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Weinberg, Daniel N., Papillon-Cavanagh, Simon, Chen, Haifen, Yue, Yuan, Chen, Xiao, Rajagopalan, Kartik N., Horth, Cynthia, McGuire, John T., Xu, Xinjing, Nikbakht, Hamid, Lemiesz, Agata E., Marchione, Dylan M., Marunde, Matthew R., Meiners, Matthew J., Cheek, Marcus A., Keogh, Michael-Christopher, Bareke, Eric, Djedid, Anissa, Harutyunyan, Ashot S., Jabado, Nada, Garcia, Benjamin A., Li, Haitao, Allis, C. David, Majewski, Jacek, Lu, Chao·2019·Nature
DOI 10.1038/s41586-019-1534-3PMC PMC6742567
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Abstract

Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis 1-4. They are also implicated in human developmental disorders and cancers 5-8, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies 9-11. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton-Brown-Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in DNMT3A. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of NSD1, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)8,12,13), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of Nsd1 and its paralogue Nsd2 in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and NSD1-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a trans-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.

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Authors
Weinberg, D. N., Papillon-Cavanagh, S., Chen, H., Yue, Y., Chen, X., Rajagopalan, K. N., Horth, C., McGuire, J. T., Xu, X., Nikbakht, H., Lemiesz, A. E., Marchione, D. M., Marunde, M. R., Meiners, M. J., Cheek, M. A., Keogh, M.-C., Bareke, E., Djedid, A., Harutyunyan, A. S., Jabado, N., Garcia, B. A., Li, H., Allis, C. D., Majewski, J., & Lu, C.
Affiliations
  • Rockefeller University (US)
  • Center for Life Sciences (CN)
  • Columbia University Irving Medical Center (US)
  • McGill University (CA)
  • University of Pennsylvania (US)
  • McGill University Health Centre (CA)
Corresponding author
  • Allis, C. David
  • Majewski, Jacek
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2019-09-04
Volume
573
Issue
7773
Pages
281-286
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-019-1534-3
PMC
PMC6742567
OpenAlex
W2972254987
Cited by
524
References
47
Citations by year
2026: 48 · 2025: 66 · 2024: 85 · 2023: 79 · 2022: 95 · 2021: 97 · 2020: 46 · 2019: 7
FWCI
20.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Cancer Institute (P01CA196539, R00CA212257, F30CA224971, P30CA013696)
  • National Institute of General Medical Sciences (T32GM008275, R44GM117683, R44GM116584, T32GM007739)
  • National Institute of Environmental Health Sciences (P30ES013508)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
Keywords
H3K36me3, DNMT3A, DNA methylation, intergenic regions, CpG methylation, NSD1, NSD2, PWWP domain, histone modifications, Sotos syndrome, Tatton-Brown-Rahman syndrome, overgrowth disorder, histone methyltransferase
MeSH terms
Protein Domains, DNA Methyltransferase 3A, Animals, Cell Line, DNA (Cytosine-5-)-Methyltransferases, Growth Disorders, Histones, Humans, Protein Binding, DNA Methylation, Protein Transport, DNA, Intergenic, Mice, Genome-Wide Association Study, Sotos Syndrome

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